Intravaginal drug delivery devices for the administration of 17β-oestradiol precursors

ABSTRACT

The invention relates to an intravaginal drug delivery device for administration to a female mammal of certain 17β-oestradiol precursors at a substantially constant rate for a period of at least three weeks. The 17β-oestradiol precursor is a 17β-oestradiol moiety in which the, or each, hydroxyl group of the 17β-oestradiol moiety is blocked by a blocking group, which blocking group is readily removed from the 17β-oestradiol in vivo. The 17β-oestradiol precursor must have either a solubility in liquid silicone of not less than 0.1 mg/100 ml or a standard k value of not less than 0.1 μg/day/mm. The 17β-oestradiol precursor must also have a solubility in distilled water of not less than 1 μg/100 ml.

This application is a 371 of PCT/IE/00063, filed Dec. 12, 1995.

This invention relates to intravaginal drug delivery devices for theadministration of 17β-oestradiol precursors. The term "17β-oestradiolprecursor" is intended to embrace certain compounds which can beconverted into 17β-oestradiol, which compounds possess physicochemicaland clinical properties as defined hereinbelow. In particular, thepresent invention relates to intravaginal drug delivery devices for theadministration of a 17β-oestradiol precursor at a substantially constantrate over a prolonged period for oestrogen-requiring conditions suchthat either the symptoms associated with hypo-oestrogenism may bealleviated or prevented or, alternatively, fertility is controlled. Moreparticularly, the invention relates to, but is not limited to, anintravaginal drug delivery device for the administration of a17β-oestradiol precursor for hormone replacement therapy in the humanfemale.

Hypo-oestrogenism in the premenopausal human female may occur due todisease, oophorectomy or traumatic injury 2!. In the postmenopausalhuman female, hypo-oestrogenism occurs as a natural consequence of theageing process. Fertility control involves the administration ofsufficient oestrogen to prevent ovulation, in effect, an inducedhyper-oestrogenism. The description hereinafter primarily concerns theutility of intravaginal drug delivery devices of the invention for thealleviation or prevention of symptoms associated with hypo-oestrogenism,specifically, hormone replacement therapy, but it will be appreciatedthat the intravaginal drug delivery devices of the invention may also beused to induce hyper-oestrogenism, specifically, to prevent ovulationand, therefore, to act as a contraceptive.

In the normal, healthy human female, 17β-oestradiol is the principaloestrogen produced by the functioning premenopausal ovary, primarily inthe ovulating follicle, during each menstrual cycle 1!. Circulating17β-oestradiol levels vary during the monthly cycle in the premenopausalhuman female, being at their highest during the peri-ovulatory phase(about 1000 pmol per liter). As ageing progresses in the human female,ovulation becomes less frequent and less predictable, resulting indiminished production of 17β-oestradiol. At the menopause, whenirreversible failure of ovarian follicular activity occurs,17β-oestradiol production decreases dramatically to less than 20 μg perday, giving circulating levels of 17β-oestradiol in serum of less than30 pg/ml 2! (1 pg/ml is equivalent to 3.676 pmol/l, assuming a molecularweight of 272 for oestradiol)

Non-oral 17β-oestradiol preparations intended for use in hormonereplacement therapy typically deliver plasma levels of 17β-oestradiolcorresponding to mean levels of the hormone in the premenopausal subjectat days 6 to 8 (about 200 pmol per liter) and days 8 to 10 (about 360pmol per liter) of the cycle. For the transdermal route, which is onenon-oral route, these plasma concentrations correspond to a dose of 50μg per day (low dose) to 100 μg per day (high dose). This is generallyaccepted as the desirable non-oral dosage range in order to provideefficaceous relief of postmenopausal symptoms whilst minimisingpotential toxicity 1!.

Hypo-oestrogenic (including postmenopausal) symptoms may be classified3! as:

(a) Neuroendocrine symptoms, characterised by one or more of thefollowing: hot flushes, night sweats, insomnia, mood changes, anxiety,irritability, loss of memory and loss of concentration.

(b) Lower urinogenital tract symptoms, characterised by one or more ofthe following: genital tract atrophy, dyspareunia, loss of libido,urethral syndrome.

(c) Miscellaneous symptoms, characterised by one or more of thefollowing: joint aches, paraesthesia, dry skin, dry or brittle hair,brittle nails.

In those cases where the combination of symptoms is sufficiently severe,it is well recognised that oestrogen hormone replacement therapy isindicated. In the postmenopausal human female requiring such therapy,the aim is to restore premenopausal oestrogen balance by delivering thenatural oestrogenic hormone, 17β-oestradiol, to the systemic circulationin a pattern that mimics its physiological secretion, that is,continuously and at a low but effectively constant rate 4!. It is wellrecognised by practitioners that hormone replacement therapy, onceinitiated in the human female, may be necessary for many years extendingfrom the onset of the menopause. A physiologically effective dose of17β-oestradiol, sufficient to provide effective control of allpostmenopausal symptoms, is considered to be at least 50 μg per day 1!,although transdermal patches delivering as low as 25 μg per day willelevate plasma oestradiol levels and are used in oestrogen replacementtherapy.

Oral administration of oestrogen, including 17β-oestradiol, for hormonereplacement therapy has a number of disadvantages 1,5!:

(a) Oral administration of a drug is followed, primarily, by absorptionthrough the gastrointestinal tract, from where the blood flow is to theliver. Some 60-90% of orally administered drug will be metabolisedduring this first pass through the liver. As a result, oral oestrogentherapy results in oestrone, a less potent oestrogen, as the predominantcirculating oestrogen.

(b) Oral therapy involves bolus doses resulting in high initialoestrogen levels which are non-physiological, a non-steady state ofcirculating serum oestrogen and a non-physiological17β-oestradiol:oestrone ratio.

Given the long-term nature of hormone replacement therapy, a drugdelivery system that promotes improved patient compliance andconvenience by reducing the dosing frequency or by requiring lessfrequent dosing is desirable. Various routes of oestrogen administrationhave been suggested, including transdermal, subcutaneous andintravaginal administration:

Oestrogens are efficiently absorbed by the transdermal route. First passeffects are avoided and a physiological 17β-oestradiol:oestrone ratio ismaintained. Transdermal administration of 17β-oestradiol is, therefore,preferable to the oral route 4!. Patient compliance and convenience arealso enhanced. However, the physical size of the transdermal drugdelivery system is such that a new device must be used every few days.This can lead to fluctuations in circulating serum oestrogen levels,which is inconvenient and has possible compliance problems for thepatient.

Subcutaneous implantation of 17β-oestradiol-loaded pellets providestherapy extending to several months and is therefore advantageous inrespect of both patient compliance and convenience. However,subcutaneous implants have a number of disadvantages 2!:

(a) A surgical procedure is required for insertion of the pellets.

(b) Infection can arise at the insertion site.

(c) The pellets are difficult to remove in the event of a problemdeveloping and any attempted removal requires a further surgicalexploration of the site.

Many of the problems associated with oestrogen delivery for hormonereplacement therapy and other long-term oestrogen-requiring conditionscan be overcome by intravaginal administration of oestrogen. It iswell-known that steroids in general, including oestrogens, areefficiently and rapidly absorbed through vaginal mucosal epithelium6,7!. The vaginal route avoids undesirable first-pass hepaticmetabolism. Delivery of oestrogen by the vaginal route is analogous tosecretion of oestrogen into the systemic circulation by the ovary.Oestrogens may be administered intravaginally by the use of creams,solutions or vaginal tablets 2!. However, to achieve controlled-releaseof the oestrogenic agent, sustained over at least one month in order toenhance both patient compliance and convenience, an intravaginal device,optionally in the shape of a ring, is the most suitable drug deliverydevice. The intravaginal ring can be self-inserted high into the vaginawhere it is held in place.

U.S. Pat. No. 3,545,439 discloses an intravaginal ring fabricated from abiocompatible organopolysiloxane elastomer and containing the steroidalcompound medroxyprogesterone acetate for the purpose of providingcontraception in the human female. There is no teaching that such adevice can be used for the administration of 17β-oestradiol precursorsat a substantially constant (or zero order pattern) rate for a period ofat least three weeks, for the treatment of long-term oestrogen-requiringconditions in general or, more specifically, for hormone replacementtherapy.

An article by Jackanicz 8! teaches that three basic designs ofintravaginal ring are possible, though additional design variations doexist:

(a) The homogeneous ring, in which the steroid is homogeneouslydistributed in a hydrophobic elastomeric system, typically a grade ofSilastic (Trade Mark), which is commercially available from Dow Corning.In this design, a high drug loading is possible and, consequently,comparatively large daily release rates are achievable over prolongedperiods. However, this design is associated with an initial high releaseof drug, producing a non-physiological level of the circulating steroidin the plasma, followed by a decline in the drug release rate as theouter portions of the ring are depleted of drug. Consequently, thisdesign of ring cannot achieve the desired pattern of a controlled,substantially constant drug release rate, which will be recognised bythose skilled in the art as zero order pattern release, over a sustainedperiod of at least three weeks, preferably several months.

(b) The shell design, in which the steroid is contained in a narrow bandor hollow annulus between a non-medicated central hydrophobicelastomeric core or central member and a narrow, outer non-medicatedhydrophobic elastomeric sheath. The outer sheath acts as a metering, orrate-controlling, membrane. With this design, burst effects are reducedcompared to the homogeneous ring. However, this design has thedisadvantage that the drug reservoir is physically limited in size andthe relative diameters of core, steroid band and rate-controlling sheathare such that, where comparatively high daily drug release rates arerequired, as in hormone replacement therapy, this design cannot achievethe desired pattern of a controlled, substantially constantcomparatively high daily drug release rate for the desired period of atleast three weeks, preferably several months. The shell design is,therefore, most suitable for contraception.

(c) The core design, in which the steroid is homogeneously mixed with ahydrophobic elastomeric polymer to form a homogeneous core, the corebeing surrounded by a rate-controlling, non-medicated hydrophobicelastomeric sheath. In this design high drug loadings are possible andthe relative diameters of core and rate-controlling sheath are such thata higher drug release rate can be achieved compared to the shell design.Burst release of drug is reduced, but not necessarily eliminated, ascompared to the homogeneous ring design. Substantially zero orderrelease can be achieved due to the presence of a rate-controlling sheathand such release can be sustained for several months due to the higherdrug loading possible with this design.

Intravaginal elastomeric rings designed to deliver 17β-oestradiol foruse in hormone replacement therapy are known.

For example, a report by Englund and co-workers 9! discloses anintravaginal elastomeric ring of shell design releasing in vitro17β-oestradiol at a rate of 200 μg per day, which corresponds to plasma17β-oestradiol levels in human female patients of from 50 to 200 pg perml. In this report, it is further disclosed that all of the human femalesubjects participating in the study had non-physiologically high17β-oestradiol plasma levels in the first 24 hours of the study periodand that there was a gradual decline in the plasma oestradiol levelsover the study period of 21 days. There is no teaching in this studythat substantially constant plasma levels of 17β-oestradiol can bemaintained even within the comparatively short-term study period of 21days, nor is there any teaching to suggest that the device could be usedfor the delivery of a suitable 17β-oestradiol precursor compound. Thisstudy, however, does state that a 17β-oestradiol release rate of 200 μgper day is too high for hormone replacement therapy in post-menopausalwomen as the resulting plasma levels of 17β-oestradiol arenon-physiological, that is, they exceed the oestrogen levels seen in thefollicular phase of fertile women. The authors conclude, in agreementwith the teaching of Lievertz 1!, that a device with a release rate of50-100 μg per day of 17β-oestradiol would provide an appropriate dosagefor hormone replacement therapy.

A study by Roy and Mishell 10! discloses an elastomeric intravaginalring comprising a polymer matrix containing a combination oflevonorgestrel and 17β-oestradiol in dimethylpolysiloxane. This studyteaches that 17β-oestradiol has a lower solubility in, and diffusionfrom, the dimethylpolysiloxane elastomer than levonorgestrel. The ringdesign in this example was of the shell type, which had an outerdiameter of 58 mm and a thickness of 9.5 mm, and released 290 μg per dayof levonorgestrel and 180 μg per day of 17β-oestradiol, respectively.The rings were studied over six or seven consecutive 21-day cycles. Ineach case, 17β-oestradiol absorption produced an initial peak for thefirst few days of each cycle, after which plasma levels declinedrapidly. The initial 17β-oestradiol serum peak was due to burst releasefrom the outer sheath, rather than from the polymer matrix, the bursteffect then building up again during each week of storage betweencycles.

Thus, the ring design disclosed in this study is unsuitable forsustained delivery of 17β-oestradiol for oestrogen-requiring conditions,including hormone replacement therapy.

A study by Stumpf et al 11! on hypo-oestrogenic women discloses anintravaginal ring of shell design intended specifically for use inhormone replacement therapy. The ring was 9.5 mm in cross-section and 54mm in diameter. The steroid band or hollow annulus contained either 100,200 or 400 mg of 17β-oestradiol. One hour after insertion, mean serum17β-oestradiol was raised to 300 pg/ml, characteristic of a burstrelease of steroid, but approached the baseline level of 24 pg/ml within24 hours. Over 1 month, the mean 17β-oestradiol level increasedminimally to about 50 pg/ml, falling back to the baseline at 2 and 3months. The authors concluded that this design fails to provideeffective therapeutic delivery of 17β-oestradiol over a sufficientlylong period as desired for hormone replacement therapy.

Stumpf et al 11! also discloses an alternative intravaginal ring ofhomogeneous design, comprising a polymer matrix containing 400 mg of17β-oestradiol in polydimethylsiloxane. This ring had a surface area of22 cm² and a cross-sectional area of 48 mm². With this ring design, theinitial serum 17β-oestradiol level was raised to about 700 pg/ml withinone hour, with the level maintained above 300 pg/ml for at least thefirst week of administration. Despite the authors' conclusion that thisring design maintains physiological oestradiol levels, it will berecognised by those skilled in the art that such levels of17β-oestradiol are non-physiological and, therefore, unacceptable foruse in the human female requiring hormone replacement therapy.

European Patent Publication No. 0 253 109 discloses an intravaginal ringof core design capable of delivering 17β-oestradiol at rates per 24hours varying from 0.5 to 25 μg per day, preferably from 4 to 8 μg per24 hours, as selected. According to the teaching therein, symptoms inthe human female arising from a hypo-oestrogenic condition can bealleviated by 17β-oestradiol delivered at these rates. These rates of17β-oestradiol delivery are substantially lower than those generallyrecognised as being required to alleviate all of the possible symptomsassociated with a hypo-oestrogenic condition--a daily delivery rate, asdetermined in vitro, of between 50 and 100 μg of 17β-oestradiol isgenerally accepted by those skilled in the art as necessary foreffective hormone replacement therapy 1! 9! 11! 12!. The symptomsreferred to in EP-A-0 253 109 relate exclusively to symptoms associatedwith the lower urinogenital tract. There is no teaching that such a lowdaily delivery rate of 17β-oestradiol can relieve neuroendocrine andother miscellaneous symptoms associated with hypo-oestrogenism in thehuman female.

Smith et al 13! teaches that daily delivery of 17β-oestradiol at a rateof between 5 and 10 μg per day, as determined in vitro, is effective atalleviating those symptoms associated with hypo-oestrogenism that relatespecifically to atrophy of vaginal and urethral epithelium. There is noteaching that other symptoms associated with hypo-oestrogenism arerelieved by such low daily doses of 17β-oestradiol.

A number of difficulties arise in incorporating 17β-oestradiol intointravaginal drug delivery devices. Specifically, the drug is too polarin its chemical character to be practically delivered in sufficientdaily quantities to alleviate all of the clinical symptoms typicallyassociated with hypo-oestrogenism in the human female and, mostparticularly, in postmenopausal females requiring hormone replacementtherapy with oestrogen. These difficulties mean that a daily drugrelease in excess of 50 μg of 17β-oestradiol, as determined in vitro, anamount clinically acknowledged as necessary for effective hormonereplacement therapy, cannot be practically achieved since:

A narrow sheath surrounding a large diameter polymer matrix is difficultto mass produce reliably to acceptable limits by methods presently knownin the art.

A high drug concentration is required in the polymer matrix of thedevice, which consequently must be of large diameter. Thus, such devicesare uneconomic to produce.

The high drug residue left after use raises environmental concerns.

It is not possible to include an additional active ingredient in knownintravaginal drug delivery devices, typically a progestogen.

According to a first aspect of the invention there is provided anintravaginal shell or core drug delivery device suitable foradministration to a female mammal, the device comprising a17β-oestradiol precursor as defined hereinbelow in a polymer matrix andhaving a sheath surrounding the polymer matrix, said device beingadapted to release the 17β-oestradiol precursor in a substantially zeroorder pattern for at least three weeks, preferably for at least threemonths and to release up to 1 mg/day 17β-oestradiol.

The 17β-oestradiol precursor must:

be a 17β-oestradiol moiety in which the, or each, hydroxyl group of the17β-oestradiol moiety is blocked by a blocking group; the, or each,blocking group being so linked to the 17β-oestradiol moiety as to bereadily removed from the 17β-oestradiol moiety in vivo and the, or each,blocking group being so chosen as to yield a substance which isnon-toxic to the female mammal, when removed from the 17β-oestradiolmoiety in vivo.

have sufficient lipophilicity as defined hereinbelow.

have sufficient hydrophilicity as defined hereinbelow.

Specifically, the 17β-oestradiol precursors must have sufficientlipophilicity as determined directly by measurement of theirsolubilities in liquid silicone (Dow Corning Grade 360 Medical Fluid) at37° C. such that their solubilities must be not less than 0.1 mg per 100ml or, alternatively, as determined indirectly by measurement ofstandard k (to be defined hereinafter) such that standard k must be notless than 0.1 μg/day/mm. Such lipophilicity is required to ensureadequate diffusion of the precursor through the device.

Specifically, the 17β-oestradiol precursors must have sufficienthydrophilicity such that their solubilities in distilled water at 20° C.are not less than 1 μg per 100 ml. Such hydrophilicity is required toensure that an adequate concentration of the precursor is achieved inthe aqueous diffusion layer between the device and the vaginalepithelium.

Precursor release from a cylindrical device of core design, whichcomprises a polymer matrix in the form of a core incorporating17β-oestradiol precursor and a sheath surrounding the core, can bedescribed by Crank's equation: ##EQU1## in which R=precursor releaserate (μg/day)

C_(S) =saturation solubility of precursor in polymer matrix (μg/ml)

D=diffusion coefficient of precursor in polymer matrix (cm² /day)

π=partition coefficient of precursor between polymer matrix and thedissolution medium

l=core length (mm)

b=sheath cross-sectional diameter (mm)

a=core cross-sectional diameter (mm)

Crank's equation relates the precursor release rate (R), in sinkconditions, to the solubility (C₂ S) and diffusibility (D) of theprecursor in the polymer matrix, its partition characteristics (π)between the polymer matrix and the dissolution medium; and the ringdimensions (l, b, a). For any given precursor in any given polymermatrix, C_(S), D and π will be constant and can be grouped together toform the composite constant, k:

    k=2C.sub.S.D.π

The k value can be empirically derived using Crank's equation in thefollowing manner: ##EQU2##

The k value is dependent on core length for certain of the17β-oestradiol precursors (see Example 6 hereinafter). Accordingly, thek value at a core length of 35 mm has been denoted "standard k" valuehereinafter.

The use of 17β-oestradiol precursors with enhanced lipophilicity,relative to 17β-oestradiol itself, is one parameter involved inovercoming the difficulties which arise in incorporating 17β-oestradiolitself into intravaginal drug delivery devices. However, only17β-oestradiol precursors possessing the above-recited additionalphysicochemical property of sufficient hydrophilicity and clinicalcharacteristics of ready in vivo conversion to 17β-oestradiol withoutyielding toxic substances as a result of that conversion, are suitablefor use in intravaginal devices for the delivery of therapeuticquantities of oestrogen to the human female for long-termoestrogen-requiring conditions, including hormone replacement therapy.In addition, such 17β-oestradiol precursors are also suitable forfertility control. Thus, for example, 17β-oestradiol-17-valerate, ahighly hydrophobic precursor, will not give detectable blood levels of17β-oestradiol in the human female when delivered intravaginally from anintravaginal drug delivery device, since its hydrophilicity or aqueoussolubility is too low. The invention therefore defines thecharacteristics of 17β-oestradiol precursors, and identifies thosesuitable precursors, such that an intravaginal drug delivery devicecontaining said precursors will deliver therapeutic quantities of17β-oestradiol to the female mammal without any of the disadvantagespreviously associated with such systems.

Whilst it will be apparent that said intravaginal drug delivery devicecan have any shape and be of any dimensions compatible both withintravaginal administration to the female mammal, including the humanfemale and with the requirements imposed by drug delivery kinetics, aparticularly preferred device according to the present invention is anintravaginal ring.

Said ring includes the outer, rate-controlling sheath surrounding thepolymer matrix in the form of a core, which sheath may be fabricatedfrom the same polymer as that of the polymer matrix or from any othersuitable, compatible polymer known in the art. Alternatively, said ringincludes the sheath surrounding the polymer matrix in the form of ahollow annulus and the device is provided with a central member withinthe annulus, which sheath and central member may each be fabricated fromthe same polymer as that of the polymer matrix or from any othersuitable, compatible polymer known in the art.

More preferably, daily release rates of the 17β-oestradiol precursorequivalent to up to 1 mg per day of 17β-oestradiol itself can besustained for up to at least 12 months in a substantially zero orderpattern.

Preferably, said intravaginal drug delivery device additionally includesa progestogen in the polymer matrix, the progestogen being selected fromthe group comprising norethisterone-17-acetate and levonorgestrel. Said17β-oestradiol precursor can be delivered in a substantially zero orderpattern for durations of at least three weeks and, preferably, up to 12months at rates of delivery equivalent to up to 1 mg per day of17β-oestradiol itself and said progestogen can be delivered for asimilar duration at rates of delivery of up to 1 mg per day.

According to a second aspect of the invention there is provided use of asuitable 17β-oestradiol precursor as defined hereinbefore for themanufacture of an intravaginal shell or core drug delivery device fordaily release of up to 1 mg 17β-oestradiol in a substantially zero orderpattern for at least three weeks and, preferably, for up to 12 monthsfor treating hypo-oestrogenic symptoms. The diameter of arate-controlling sheath is such that it can be manufactured withinacceptable tolerances by methods presently known in the art.

According to a third aspect of the invention there is provided a processfor the preparation of an intravaginal shell or core drug deliverydevice suitable for administration to a female mammal. Said processcomprises the steps of combining a suitable 17β-oestradiol precursor asdefined hereinabove, a polymer, a suitable cross-linking agent and acuring catalyst to form a mix; curing the mix to form the polymermatrix; and providing a sheath surrounding the polymer matrix.

Alternatively, the polymer matrix forms a hollow annulus and the processcomprises the steps of forming a central member; combining the17β-oestradiol precursor with the polymer, the suitable cross-linkingagent and the curing catalyst to form the mix and curing the mix to formthe polymer matrix in the form of the hollow annulus surrounding thecentral member; and providing the sheath surroundiong the polymermatrix. The relative amounts of the respective polymer matrix and sheathcomponents are chosen, and the geometry of the ring components selected,in order to provide a daily release of 17β-oestradiol precursorequivalent to between 50 and 250, and most preferably between 50 and100, μg per day of 17β-oesstradiol.

According to a fourth aspect of the invention there is provided use of asuitable 17β-oestradiol precursor as defined hereinabove in anintravaginal shell or core drug delivery device for release of up to 1mg/day 17β-oestradiol in a substantially zero order pattern for at leastthree weeks and, preferably, for up to 12 months.

According to the present invention, a particularly preferred group of17β-oestradiol precursors are those possessing one or more acyl groupsesterically linked as blocking groups to the hydroxyl groups of the17β-oestradiol moiety. Preferably, the, or each, blocking group is analiphatic short-chain acyl group with the proviso that, when the acylgroup is acetyl, each hydroxyl group cannot be blocked with acetyl. Morepreferably, the acyl group is the acyl moiety of a saturated orunsaturated monocarboxylic or dicarboxylic acid. The one or more acylgroups may block the 3-position and/or the 17-position of the17β-oestradiol moiety. It will be known to those skilled in the art thattherapeutically active esters are rapidly hydrolysed in human plasma bynon-specific esterases to the corresponding parent acid and alcohol. Inthe case of 17β-oestradiol precursors, it will be apparent to thoseskilled in the art that hydrolysis of said precursors in human plasmawill yield 17β-oestradiol itself, together with one or more acidiccomponents, the number of such acidic components depending on the numberof acyl groups present per molecule of said precursor. Said acyl groupsinclude saturated aliphatic short-chain (C1-5) straight or branchedmono- and dicarboxylic acids such as formyl, acetyl, propionyl, butyryl,isobutyryl, oxalyl, malonyl, glutaryl and succinyl; unsaturatedaliphatic short-chain (C2-5) straight or branched mono- and dicarboxylicacids such as acryloyl, propioloyl, methacryloyl, crotonoyl,isocrotonoyl, maleoyly fumaroyl, citraconoyl and mesaconoyl; carbocycliccarboxylic acids or other such groups known to those skilled in the art.Such acyl groups are disclosed by way of example only and it will beunderstood that the scope of the invention is not limited in any way bysuch disclosure.

The preferred 17β-oestradiol precursors must have sufficient lipophiliccharacter such that their solubilities in liquid silicone (Dow CorningGrade 360 Medical Fluid) at 37° C. are not less than 0.1 mg per 100 ml.Alternatively, the preferred 17μ-oestradiol ester precursors must havesufficient lipophilic character such that their standard k values (asdefined hereinabove) are not less than 0.1 μg/day/mm.

Further, said precursors must have a hydrophilic character such thattheir solubilities in distilled water at 20° C. are not less than 1 μgper 100 ml. 17β-oestradiol-3-benzoate and 17β-oestradiol-17-valerate areexamples of 17β-oestradiol precursors not possessing the requisiteaqueous solubility.

Although not essential for the purposes of the invention, saidprecursors should, preferably, be micronised.

According to the present invention, a preferred acyl group is acetyl orpropionyl and particularly preferred 17β-oestradiol precursors are17β-oestradiol-17-acetate, 17β-oestradiol-3-acetate,17β-oestradiol-17-propionate and 17β-oestradiol-3-propionate.

According to the present invention, the acyl group preferably blocks the3-position, so that particularly preferred 17β-oestradiol precursors are17β-oestradiol-3-acetate and 17β-oestradiol-3-propionate.17β-oestradiol-3-acetate is most particularly preferred.

Suitable progestogens for use in the intravaginal drug delivery devicesof the present invention include, but are not limited to, levonorgestreland norethisterone-17-acetate. Further suitable progestogens would beexpected to include chlormadinone, desorgestrel, gestodene,medroxyprogesterone, megestrol, norgestimate and progesterone.

The intravaginal ring may be constructed from one or more biocompatiblepolymers, for example, elastomers, compatible with said 17β-oestradiolprecursors, such as organopolysiloxanes or polyurethanes. Where theelastomer is chosen from the room-temperature vulcanising type ofhydroxyl-terminated organopolysiloxanes, suitable cross-linking agentsand curing catalysts known in the art may be required.Dimethylpolysiloxane compositions may also be used as the elastomericcomponent of the intravaginal drug delivery device of the invention.

The geometry of the intravaginal drug delivery device of the inventionmay be chosen such that the daily release of the 17β-oestradiolprecursor can be varied up to 1 mg per day, expressed as 17β-oestradiolitself, and preferably from between 50 to 100 μg per day, againexpressed as 17β-oestradiol itself. Said ring geometries can also bevaried to permit the simultaneous delivery, at therapeutically desirablerates, from an individual intravaginal drug delivery device, of asuitable 17β-oestradiol precursor and a progestogenic substance. Theterm "geometry" encompasses the overall diameter of the ring; thecross-sectional diameter of the ring; the ratio of the core diameter tothe diameter of the whole device in cross-section; and the length of thecore.

The percentage loading of 17β-oestradiol precursor contained in the corecan vary from 1% (w/w) to in excess of 50% (w/w) and is only limited bythe physical characteristics of the final mix. It will be apparent tothose skilled in the art that the only importance of said drug loadingin a device of core or shell design with an outer, rate-controllingsheath is to ensure that there is sufficient drug present at all timesto allow a substantially zero order pattern of drug release to bemaintained throughout the required period of sustained drug release.Thus, to ensure maintenance of the substantially zero order drug releasepattern throughout the lifetime of the device, the necessary drugloading will be sufficiently in excess of the total drug required to bedelivered over the defined sustained-release period.

Several embodiments of the invention will now be demonstrated byreference to the following General Method of Manufacture of anintravaginal drug delivery device in the form of a ring for the deliveryof a suitable 17β-oestradiol precursor as defined hereinabove, eitheralone or in combination with a progestogenic substance. This GeneralMethod of Manufacture is exemplified by reference to Examples 1 to 10.It should be understood that these examples are disclosed solely by wayof further illustrating the invention and should not be taken in any wayto limit the scope of said invention. Thus, for instance, it will beobvious to those skilled in the art that the technique of injectionmoulding referred to in the General Method of Manufacture may bereplaced in whole or in part by other manufacturing techniques, forexample, extrusion, that will produce a similar end product.

General Method of Manufacture: Core Design

An elastomer mix is prepared by blending 97 parts by weight of ahydrophobic elastomeric polymer containing about 25% (w/w) diatomaceousearth as the filler with 2.5 parts by weight of a cross-linking agent,n-propylorthosilicate. A suitable hydrophobic elastomeric polymer isstannous octoate-cured polydimethylsiloxane polymer, two suitableexamples of which are those known as Dow Corning QCF7 3099 and Nusil Med7.6382.

The elastomer mix thus formed is further blended in the ratio of 85parts by weight of the elastomer mix, 5 parts by weight of bariumsulphate and 10 parts by weight of a 17β-oestradiol precursor,preferably a 17β-oestradiol ester, more preferably,17β-oestradiol-3-acetate, 17β-oestradiol-17-acetate,17β-oestradiol-3-propionate or 17β-oestradiol-17-propionate. Thereby, anactive mix is formed.

The core of the intravaginal drug delivery device of the invention isproduced by mixing 200 parts by weight of the active mix with 1 part byweight of an activating catalyst, for example, stannous octoate. Theresultant core mix is injected into a core mould and cured at 80° C. for2 minutes. The mould is then opened, following which the core is removedand trimmed.

An intravaginal drug delivery device in the form of a half ring isproduced by mixing 200 parts by weight of elastomer mix with 1 part byweight of an activating catalyst, for example, stannous octoate. Theresultant half ring mix is injected into a half ring mould containing acore previously prepared as described in the immediately precedingparagraph and cured at 80° C. for 2 minutes. The mould is then opened,following which the half ring is removed and trimmed.

An intravaginal drug delivery device in the form of a complete ring isproduced by mixing 200 parts by weight of elastomer mix with 1 part byweight of an activating catalyst, for example, stannous octoate. Theresultant full ring mix is injected into a full ring mould containing ahalf ring previously prepared as described in the immediately precedingparagraph and cured at 80° C. for 2 minutes. The mould is then opened,following which the full ring is removed and trimmed.

The geometric characteristics of the ring can be varied as required bythe use of appropriately sized moulds, as exemplified by the followingexamples, or by the use of appropriately sized extrusion nozzles, aswill be obvious to those skilled in the art.

EXAMPLE 1

An intravaginal drug delivery device in the form of a ring having anominal in vitro daily release rate of 10 μg per day of17β-oestradiol-17-acetate was prepared with a ring geometry as describedin Table 1, by following the General Method of Manufacture set outhereinabove.

EXAMPLE 2

An intravaginal drug delivery device in the form of a ring having anominal in vitro daily release rate of 50 μg per day of17β-oestradiol-17-acetate was prepared with a ring geometry as describedin Table 1, by following the General Method of Manufacture set outhereinabove.

EXAMPLE 3

An intravaginal drug delivery device in the form of a ring having anominal in vitro daily release rate of 50 μg per day of17β-oestradiol-3-acetate was prepared with a ring geometry as describedin Table 1, by following the General Method of Manufacture set outhereinabove.

EXAMPLE 4

An intravaginal drug delivery device in the form of a ring having anominal in vitro daily release rate of 100 μg per day of17β-oestradiol-3-acetate was prepared with a ring geometry as describedin Table 1, by following the General Method of Manufacture set outhereinabove.

EXAMPLE 5

An intravaginal drug delivery device in the form of a ring having anominal daily in vitro release rate of, simultaneously, 50 μg per day of17β-oestradiol-3-acetate and 20 μg per day of the progestogenicsubstance, levonorgestrel, was prepared with a ring geometry asdescribed in Table 1, by following the General Method of Manufacture setout hereinabove.

The nominal in vitro release rates set out in Table 1 for the rings ofExamples 1-5 were determined under sink conditions of 1% (w/v)benzalkonium chloride. These release rates were determined in thefollowing manner.

Each ring (n=4) was suspended in the dissolution medium in an individualflask which is then capped, placed in a suitable oven at 37° C. andshaken. The dissolution medium was changed every 24 hours (±30 minutes).An aliquot of the used dissolution medium was analysed by highperformance liquid chromatography (HPLC) using reverse phase packing andUV detection (at 235 nm for 17β-oestradiol-3-acetate and for

                                      TABLE 1    __________________________________________________________________________    Drug-loaded core dimensions for intravaginal    rings, 9 × 54 mm, having a nominal in vitro daily    release, in sink conditions, of a 17β-oestradiol precursor,    either alone or in combination with a progestogen.                                 Core dimensions (mm)                     Nominal daily release (μg)                                 as cross-sectional    Active ingredient                Example                     (in vitro)  diameter × length    __________________________________________________________________________    17β-oestradiol-17-acetate                1    10          2 × 15    17β-oestradiol-17-acetate                2    50          2 × 75    17β-oestradiol-3-acetate                3    50          2 × 8    17β-oestradiol-3-acetate                4    100         2 × 16    17β-oestradiol-3-acetate                5    50 E3A and 20 LN                                 2 × 8(E3A)    (E3A) in combination with    3 x 105(LN)    levonorgestrel (LN)    __________________________________________________________________________

17β-oestradiol-3-propionate; at 281 nm for 17β-oestradiol-17-acetate,for 17β-oestradiol-17-propionate and for 17β-oestradiol), with referenceto the appropriate standard solutions. Due to hydrolysis to17β-oestradiol during storage, 17β-oestradiol-3-acetate levels weredetermined by analysis for both 17β-oestradiol and17β-oestradiol-3-acetate. An improved analytical method was subsequentlydeveloped for 17β-oestradiol-3-acetate--this involves hydrolysing analiquot of used dissolution medium with 0.5N NaOH to yield17β-oestradiol with subsequent buffering prior to injection into theHPLC system for detection at 281 nm of the hydrolysis product,17β-oestradiol, with reference to the appropriate standard solutions.

The original analytical method has a precision of less than 2% RSD(relative standard deviation) for 17β-oestradiol and for the17β-oestradiol precursors, with the exception of17β-oestradiol-3-acetate for which the original and improved analyticalmethods had precisions of less than 4% RSD and less than 2% RSD,respectively. The sensitivity of the original and improved analyticalmethods is 5 μg/100 ml.

Re-analysis of the daily in vitro release rate data for17β-oestradiol-3-acetate given in Table 1 from the original method,yields altered daily release rates which, in turn, result in correctedprecursor-containing core dimensions of 2×10 mm, 2×20 mm and 2×10 mmrespectively, for the rings of Examples 3-5, in order to nominallyrelease 50 μg, 100 μg and 50 μg/day, respectively, of the activeingredient, 17β-oestradiol-3-acetate.

EXAMPLE 6 Mean Daily In Vitro Release Rates over 90 Days (Maximum)

The in vitro dissolution characteristics of the intravaginal rings ofthe invention, which contain various 17β-oestradiol precursors, and ofan intravaginal ring containing 17β-oestradiol itself are illustrated byreference to Table 2. Four identical rings were prepared for eachcompound according to the General Method of Manufacture, the elastomermix having a stannous octoate-cured polydimethylsiloxane polymer as thehydrophobic elastomeric polymer. In all cases the ring geometriescomprise a ring of dimensions 9 mm (cross-sectional diameter)×54 mm(outer diameter) and containing a full length core (141 mm) ofcross-sectional diameter 2 mm. The rings were tested in vitro at aconstant temperature of 37° C. for their release characteristics in asufficient volume of each of the following media: 0.9% (w/v) saline,0.133% (w/v) aqueous benzalkonium chloride and 1.0% (w/v) aqueousbenzalkonium chloride. The saline medium was chosen because the abilityof a particular 17β-oestradiol precursor to achieve substantial releasefrom an intravaginal ring into saline may be regarded as a significantindicator of its likely in vivo absorption characteristics. The salineand benzalkonium chloride-containing media were chosen to ensure `sinkconditions` in at least one medium for each intravaginal ring. It willbe recognised by those skilled in the art that the term `sinkconditions` refers to that set of experimental conditions in vitro whicheffectively simulates the active haemoperfusion that occurs in vivo, andwhich results in a maximum drug concentration gradient and maximum drugdiffusion

                  TABLE 2    ______________________________________    Mean daily release rates of 17β-oestradiol and    17β-oestradiol precursors from intravaginal rings into    various media. Rings were 9 × 54 mm containing a drug-    loaded core of full length (141 mm) having a cross-sectional    diameter of 2 mm.              Mean Daily Release              μg per day (N = 4)              Release Medium                0.9% (w/v)                          0.133% (w/v)                                      1.0% (w/v)    Active ingredient                saline    BKC*        BKC*    ______________________________________    17β-oestradiol                8         --          --    17β-oestradiol-17-                **        365         550    valerate    17β-oestradiol-17-                26        112         218    propionate    17β-oestradiol-17-                24        S6          96    acetate    17β-oeastradiol-3-                <5        42          66    17β-oestradiol-3-                350       700         850    acetate    17β-oestradiol-3-                --        --          1200    propionate    ______________________________________     *BKC = benzalkonium chloride in aqueous solution     **Not detected     -- Not determined

rate, at any given time, across the aqueous boundary layer. Thus, an invitro dissolution experiment can be designed such that the solutionsolubility of the released drug in the dissolution medium is muchgreater than its bulk concentration in this medium at any given time,for example, by micellar drug solubilisation due to incorporation of asurfactant such as benzalkonium chloride (BKC), at a concentration aboveits critical micelle concentration.

Thus, each ring was suspended by a thread in an individual closed flaskcontaining the dissolution medium, maintained at a constant temperatureof 37° C. The contents of the flask were gently agitated in order toprevent the occurrence of a hydrostatic layer on the surface of thering. After 24 hours, the ring was removed and suspended in a flask offresh dissolution medium of identical volume by a method identical tothat previously described. This process was repeated at each successive24 hour interval until a total maximum time of 90 days had elapsed. Atthe end of each 24 hour period, a sample of the dissolution medium wasimmediately analysed, as desired, for its precurser content by asuitable analytical method, typically by high performance liquidchromatography (see Example 5).

The data in Table 2 refer to mean daily in vitro release rates of17β-oestradiol and various 17β-oestradiol precursors as determined bythe method described, in each of the three specified release media, overa continuous period of up to 90 days. Sink conditions were evident forthe 17β-oestradiol precursors in 1.0% BKC. The low release rates intosaline of the more lipophilic 17β-oestradiol precursors, the valerateand benzoate esters, were due to their intrinsically low aqueoussolubilities. The best release rates under sink conditions, incombination with substantial aqueous solubilities as indicated by therelease rates into saline, were observed for the acetate and propionateesters. Thus, in particular, 17β-oestradiol-3-acetate exhibitedsubstantial release, in both BKC and in saline, from intravaginal ringsof ring geometry as described in Table 2.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 of the accompanying drawings shows the in vitro daily release of17β-oestradiol-17-acetate (as 17β-oestradiol) from a 9×54 mmintravaginal ring (core length of 141 mm and core cross-sectionaldiameter of 2 mm) over 90 days into a 1.0% (w/v) aqueous solution ofbenzalkonium chloride. The ring was prepared by following the GeneralMethod of Manufacture set out hereinabove.

FIG. 2 of the accompanying drawings shows the in vitro daily releasefrom a 7.6×56 mm ring of 17β-oestradiol-3-acetate (as 17β-oestradiol(core length 35 mm; core cross-sectional diameter 2 mm)) andnorethisterone-17-acetate (core length 90 mm; core cross-sectionaldiameter 2 mm) over 12 days into a 1.0% (w/v) aqueous solution (250 ml)of benzalkonium chloride. The ring was prepared by following the GeneralMethod of Manufacture set out hereinabove.

The data presented in the figures confirm the efficacy of intravaginaldrug delivery devices according to the present invention in releasing17β oestradiol in vitro in a substantially zero order pattern over theup to 90 day period of study.

                  TABLE 3    ______________________________________    Mean daily release rates of 17β-oestradiol precursors into 250 ml of    1%    (w/v) benzalkonium chloride. Rings were 9 × 54 mm containing a    drug-    loaded core of varying length having a cross-sectional diameter of 2 mm.                           Mean Daily Release                Core length                           (μg/day) (n = 5)    Active ingredient                (mm)       (as precursor)*                                         k    ______________________________________    17β-oestradiol-3-                6          49.25         12.347    acetate     12         91.88         11.517                25         177.15        10.658                35         236.66        10.017    17β-oestradiol-3-                35         300.00        12.89    propionate  70         600.00        12.89                140        1200.00       12.89    17β-oestradiol-17-                35         19.50         0.8380    acetate     70         40.94         0.8797                140        87.45         0.9395    17β-oestradiol-17-                17         24.08         2.130    propionate  35         42.86         1.842                70         83.54         1.795                140        155.20        1.667    ______________________________________     *The release rate data for 17oestradiol-3-acetate are based on the amount     of anhydrous 17oestradiol detected by the improved analytical method.     These data have been converted to 17oestradiol as 17oestradiol-3-acetate     by multiplication by the correction factor 1.154.

Intravaginal drug delivery devices in the form of rings were prepared,each with a ring geometry as described in Table 3, by following theGeneral Method of Manufacture set out hereinabove. Table 3 also shows invitro release rates into 1% (w/v) benzalkonium chloride for these ringsand the apparent k values observed when the core length is varied.

The dissolution medium was changed daily, following the protocol set outhereinabove. Mean daily release rates from the second week ofdissolution experiments were used to determine the apparent k valuespresented in Table 3.

It will be observed that the apparent k value varies with core lengthfor 17β-oestradiol-3-acetate, 17β-oestradiol-17-acetate and17β-oestradiol-17-propionate. It was, therefore, decided to determine kvalues at a core length of 35 mm and such k values are hereinafterreferred to as "standard k" values.

EXAMPLE 7 Solubility Parameters for 17β-Oestradiol and Certain17β-Oestradiol Precursors

The standard k value was determined from the mean daily release ratesobserved in Example 6. The dissolution medium of 1.0% (w/v) of anaqueous solution of benzalkonium chloride was used in respect of thevarious 17β-oestradiol precursors, so as to ensure sink conditions. Therelevant data are presented in Table 4.

Aqueous solubility was determined at 20° C. in distilled water. Therelevant data are presented in Table 5.

Silicone solubility was determined at 37° C. in Dow Corning (Trade Mark)360 medical fluid. The relevant data are presented in Table 5.

EXAMPLE 8 In Vitro Plasma Hydrolysis

The stability of 17β-oestradiol-3-acetate and 17β-oestradiol-17-acetatewere determined in human blood by incubation at 37° C. at concentrationsof 100 pg/ml and 500 pg/ml--these concentrations were chosen to be ofthe same order or slightly higher than circulating 17β-oestradiol levelsexpected from use of an intravaginal drug delivery device according tothe invention. In addition, a supranormal concentration of 10 ng/ml wasalso investigated.

Samples were collected at 1, 5, 10, 15, 30 and 60 minutes and at 2, 4, 6and 24 hours after commencement of incubation. On collection of eachsample, the reaction was stopped by the addition of sodium fluoride(0.05-0.1M final concentration), the plasma separated by centrifugationand analysed for 17β-oestradiol using ELISA on a Behring OPUS Plusinstrument, by reference to the appropriate standard solutions.

The hydrolysis half-lives for 17β-oestradiol-3-acetate and17β-oestradiol-17-acetate were <1 minute and 4 hours, respectively.

EXAMPLE 9 In Vivo Characteristics

The in vivo dissolution characteristics of intravaginal drug deliverydevices according to the invention were assessed in the followingmanner.

                  TABLE 4    ______________________________________    Mean daily release rates of 17β-oestradiol precursors from    intravaginal    rings into various media. Rings were 9 × 54 mm containing a    drug-loaded    core of 35 mm length having a cross-sectional diameter of 2 mm.                 Mean Daily Release                 (μg/day) (n = 5)                 Release medium                   0.9% (w/v)                             1.0% (w/v)    Active ingredient                   saline    BKC       Standard k    ______________________________________    17β-oestradiol-3-                   --        236.66    10.017    acetate    17β-oestradiol-3-                   250-350   300.00    12.89    propionate    17β-oestradiol-17-                   --        19.50     0.838    acetate    17β-oestradiol-17-                   --        42.86     1.842    propionate    ______________________________________     -- not determined

                  TABLE 5    ______________________________________                   Aqueous   Silicone                   solubility                             solubility                                       k    Active Ingredient                   (μg/100 ml)                             (mg/100 ml)                                       (μg/day/mm)    ______________________________________    17β-Oestradiol                   190       1.63.sup.1                                       0.09***    17β-Oestradiol-17-valerate                   *         15.02.sup.1                                       5.86***    17β-Oestradiol-17-propionate                    5        --        1.842**    17β-Oestradiol-17-acetate                    12       1.7       0.838**    17β-Oestradiol-3-benzoate                   *         3.68.sup.1                                       0.70***    17β-oestradiol-3-acetate                   380       18.6      10.017**    17β-Oestradiol-3-propionate                   230       30.0      12.89**    ______________________________________     *not detected     -- not determined     **standard k     ***k using core of 141 mm length     .sup.1 compiled from Novel Drug Delivery Systems; Yie W. Chien; Marcel     Dekker, Inc.

Intravaginal rings containing the 17β-oestradiol precursors,17β-oestradiol-3-acetate or 17β-oestradiol-17-acetate, were preparedaccording to the General Method of Manufacture, having a stannousoctoate-cured polydimethylsiloxane polymer as the hydrophobicelastomeric polymer. The 9×54 mm rings have nominal in vitro dailyrelease rates of 115-125 or 230-250 μg (each calculated as anhydrous17β-oestradiol) or 100 μg (hereinafter referred to as "120 μg" or "240μg" or "100 μg" rings, respectively), by virtue of respective coredimensions of 2×24 mm and 2×47 mm and 2×141 mm (cross-sectionaldiameter×length).

Several female post-menopausal subjects, who gave informed consentbefore participation, entered a randomised cross-over study of 18 weeksduration in which, following a run in period of 2 weeks (for baselineplasma oestradiol determinations), each subject successively receivedeach of a 100 μg, 120 μg and 240 μg ring, with a washout period of 2weeks between successive rings. The rings were inserted on Day 0 andremoved on Day 28. Plasma 17β-oestradiol levels were regularly measuredduring the run in period before the start of the study, immediatelypreceding insertion on Day 0 and for the following four week periodending on Day 28, when the ring was removed. The observed mean plasma17β-oestradiol levels are set out in Tables 6, 7 and 8.

                  TABLE 6    ______________________________________    120 μg ring (n = 5): 17β-Oestradiol-3-Acetate              Mean Plasma 17β-Oestradiol level    Day       (pmol/l)    ______________________________________    -14       46.0    -10       49.6    -5        43.0    0         48.6    2         431.0    4         394.4    7         364.0    9         359.8    11        350.0    14        371.8    18        321.4    21        338.8    28        284.0    ______________________________________

It will be observed that the mean baseline 17β-oestradiol level was 46.8pmol/l and that the mean 17β-oestradiol level, post-ring insertion, was357.24 pmol/l. Thus, the 120 μg ring according to the inventiondelivered a mean increase in plasma 17β-oestradiol of 310.4 pmol/l overthe 28 day study period.

                  TABLE 7    ______________________________________    240 μg ring (n = 5): 17β-Oestradiol-3-Acetate    Mean Plasma 17β-Oestradiol level            Day   (pmol/l)    ______________________________________            -14   46.0            -10   49.6            -5    43.0            0     35.8            2     817.4            4     697.2            7     676.6            9     667.8            11    645.0            14    671.2            18    667.2            21    642.8            28    665.2    ______________________________________

It will be observed that the mean baseline 17β-oestradiol level was 43.6pmol/l and that the mean 17β-oestradiol level, post-ring insertion, was683.37 pmol/l. Thus, the 240 μg ring according to the invention,delivered a mean increase in plasma 17β-oestradiol of 639.7 pmol/l overthe 28 day study period.

                  TABLE 8    ______________________________________    100 μg ring (n = 4): 17β-Oestradiol-17-Acetate              Mean Plasma 17β-Oestradiol level    Day       (pmol/l)    ______________________________________    -14       46.00    -10       49.60    -5        43.00    0         55.75    2         193.00    4         110.25    7         103.25    9         91.25    11        89.50    14        95.75    18        87.25    21        104.00    28        102.50    ______________________________________

It will be observed that the mean baseline 17β-oestradiol level was48.59 pmol/l and that the mean 17β-oestradiol level, post-ringinsertion, was 108.53 pmol/l. Thus, the 100 μg ring according to theinvention, delivered a mean increase in plasma 17β-oestradiol of 59.94pmol/l over the 28 day study period.

It will be appreciated that the 120 μg and 240 μg rings of the presentinvention will be suitable for the alleviation or prevention of symptomsassociated with hypo-oestrogenism, specifically hormone replacementtherapy and for inducing hyper-oestrogenism, specifically to preventovulation. It will also be appreciated that the 100 μg ring of thepresent invention will be suitable for hypo-oestrogenism responding tolow dose hormone replacement therapy and that a ring having a largercore diameter would, of course, release more oestradiol precursor and,therefore, deliver more 17β-oestradiol into the blood stream.

The data presented in Tables 6-8 confirm the efficacy of intravaginaldrug delivery devices according to the present invention in releasing17β-oestradiol into the blood stream in a substantially zero orderpattern over the 28 day period of study.

EXAMPLE 10 In Vivo Characteristics

Intravaginal rings containing the 17β-oestradiol precursor,17β-oestradiol-3-acetate, were prepared according to the General Methodof Manufacture, having a stannous octoate-cured polydimethylsiloxanepolymer as the hydrophobic elastomeric polymer. The 9×54 mm rings have anominal in vitro daily release rate of 57.5-62.5 μg calculated asanhydrous 17β-oestradiol (hereinafter referred to as a "60 μg" ring) byvirtue of dimensions of 2×12 mm (cross-sectional diameter×length).

Six female post-menopausal subjects, who gave informed consent beforeparticipation, received the 60 μg intravaginal ring. These rings wereinserted on Day 0 and removed on Day 14. Plasma 17β-oestradiol levelswere measured on Day 0 and regularly during the two week period and theresults are set out in Table 9.

                  TABLE 9    ______________________________________    60 μg ring (n = 6): 17β-Oestradiol-3-Acetate               Mean Plasma 17β-oestradiol    Day        level (pmol/l)    ______________________________________    0          31.5    2          229.3    4          146.8    7          131.5    9          139.8    11         114.8    14         134.7    ______________________________________

It will be observed that the mean baseline 17β-oestradiol level was 31.5pmol/l and that the mean 17β-oestradiol level, post-ring insertion, was149.48 pmol/l. Thus, the 60 μg ring according to the present invention,delivered a mean increase in plasma 17β-oestradiol of 117.98 pmol/l overthe 14 day study period.

It will be appreciated that the 60 μg ring of the present invention willbe suitable for the alleviation or prevention of symptoms associatedwith hypo-oestrogenism, specifically, hormone replacement therapy.

It will also be appreciated that the 60 μg ring of the present Exampleand the 120 and 240 μg rings of Example 9 demonstrate a corelength-dependent delivery of 17β-oestradiol into the blood stream in asubstantially zero order pattern. The core length can, therefore, beadjusted to yield the desired incremental plasma 17β-oestradiol level totreat symptoms associated with hypo-oestrogenism or to inducehyper-oestrogenism.

REFERENCES CITED

1. Lievertz, R. W. (1987) Pharmacology and pharmacokinetics ofestrogens. American Journal of Obstetrics and Gynecology vol. 156, pp.1289-1293.

2. Stumpf, P. G. (1990) Pharmacokinetics of estrogen. Obstetrics andGynecology vol. 75 (suppl.), pp 9S-14S.

3. Marsh, M. S. and Whitehead, M. I. (1992) Management of the menopause.British Medical Bulletin vol. 48, pp. 426-457.

4. Place, V. A. et al. (1985) A double-blind comparative study ofEstraderm and Premarin in the amelioration of postmenopausal symptoms.American Journal of Obstetrics and Gynecology vol. 152, pp. 1092-1099.

5. Kuhl, H. (1990) Pharmacokinetics of oestrogens and progestogens.Maturitas vol. 12, pp. 171-197.

6. Chien, Y. W. (1992) Vaginal Drug Delivery and Delivery Systems. In:Novel Drug Delivery Systems, 2nd edn. Marcel Dekker, New York, pp.529-584.

7. Rigg, L. A. et al. (1978) Absorption of estrogens from vaginalcreams. New England Journal of Medicine vol. 298, pp. 195-197.

8. Jackanicz, T. M. (1979) Vaginal ring steroid-releasing systems. InLong-Acting Contraceptive Delivery Systems (Zatuchni, G. I. et al.,eds.). Harrow and Row, Philadelphia, pp. 201-212.

9. Englund, D. E. et al. (1981) Pharmacokinetics and pharmacodynamiceffects of vaginal oestradiol administration from silastic rings inpostmenopausal women. Maturitas vol. 3, pp. 125-133.

10. Roy, S. and Mishell, D. R. (1983) Vaginal ring clinical studies:update. In: Long-Acting Contraceptive Delivery Systems (Zatuchni, G. I.et al., eds.). Harrow and Row, Philadelphia, pp. 581-594.

11. Stumpf, P. G. et al. (1982) Development of a vaginal ring forachieving physiologic levels of 17β-estradiol in hypoestrogenic women.Journal of Clinical Endocrinology and Metabolism vol. 54, pp. 208-210.

12. Stumpf, P. G. (1986) Selecting constant serum estradiol levelsachieved by vaginal rings. Obstetrics and Gynecology vol. 67, pp. 91-94.

13. Smith, P. et al. (1993) Oestradiol-releasing vaginal ring fortreatment of postmenopausal urogenital atrophy. Maturitas vol. 16, pp.145-154.

I claim:
 1. A cylindrical intravaginal drug delivery device suitable foradministration to a female mammal, the device comprising a17β-oestradiol precursor in a biocompatible hydrophobic elastomericpolymer matrix, the device releasing the 17β-oestradiol precursor in asubstantially zero order pattern for at least three weeks, the precursorbeing a 17β-oestradiol moiety in which the, or each, hydroxyl group ofthe 17β-oestradiol moiety is blocked by a blocking group, the precursorhaving sufficient lipophilicity as determined either by a solubility inliquid silicone of not less than 0.1 mg/100 ml or by a standard k value,in which k=2C_(S) Dπ, of not less than 0.1 μg/day/mm, the precursorhaving sufficient hydrophilicity as determined by a solubility indistilled water of not less than 1 μg/100 ml, the, or each, blockinggroup being so linked to the 17β-oestradiol moiety as to be readilyremoved from the 17β-oestradiol moiety in vivo, and the, or each,blocking group being so chosen as to yield a substance which isnon-toxic to the female mammal when removed from the 17β-oestradiolmoiety in vivo wherein C_(S) corresponds to the precursor's saturationsolubility in the polymer matrix and D corresponds to the precursor'sdiffusion coefficient in the polymer matrix.
 2. An intravaginal drugdelivery device according to claim 1, in which the, or each, blockinggroup is an aliphatic C₁₋₅ acyl group, with the proviso that, when theacyl group is acetyl, each hydroxyl group cannot be blocked with acetyl.3. An intravaginal drug delivery device according to claim 2, in whichthe acyl group is the acyl moiety of a saturated monocarboxylic ordicarboxylic acid.
 4. An intravaginal drug delivery device according toclaim 3, in which the acyl group is selected from the group comprisingformyl, acetyl, propionyl, butyryl, isobutyryl, oxalyl, malonyl,succinyl and glutaryl.
 5. An intravaginal drug delivery device accordingto claim 2, in which the acyl group is the acyl moiety of an unsaturatedmonocarboxylic or dicarboxylic acid.
 6. An intravaginal drug deliverydevice according to claim 5, in which the acyl group is selected fromacryloyl, propioloyl, methacryloyl, crotonoyl, isocrotonoyl, maleoyl,fumaroyl, citraconoyl and mesaconoyl.
 7. An intravaginal drug deliverydevice according to claim 1, in which the blocking group blocks the3-hydroxyl group of the 17β-oestradiol moiety.
 8. An intravaginal drugdelivery device according to claim 1, in which the blocking group blocksthe 17-hydroxyl group of the 17β-oestradiol moiety.
 9. An intravaginaldrug delivery device according to claim 7, in which the blocking groupis selected from acetyl or propionyl.
 10. An intravaginal drug deliverydevice according to claim 7, in which the precursor is17β-oestradiol-3-acetate or 17β-oestradiol-3-propionate.
 11. Anintravaginal drug delivery device according to claim 8, in which theprecursor is 17β-oestradiol-17-acetate or 17β-oestradiol-17-propionate.12. An intravaginal drug delivery device according to claim 1, in whichthe device additionally includes a progestogen in the polymer matrix.13. An intravaginal drug delivery device according to claim 12, in whichthe progestogen is selected from the group comprisingnorethisterone-17-acetate and levonorgestrel.
 14. An intravaginal drugdelivery device according to claim 1 suitable for inducinghyper-oestrogenism including fertility control, in which the polymermatrix forms a hollow annulus and the device is provided with a centralmember within the annulus and a sheath surrounding the polymer matrix.15. A process for the preparation of a cylindrical intravaginal drugdelivery device for release in a substantially zero order pattern for atleast three weeks and suitable for administration to a female mammal,the process comprising the steps of:combining a 17β-oestradiolprecursor, the precursor being a 17β-oestradiol moiety in which the, oreach, hydroxyl group of the 17β-oestradiol moiety is blocked by ablocking group; the precursor having sufficient lipophilicity asdetermined either by a solubility in liquid silicone of not less than0.1 mg/100 ml or by standard k value as defined hereinabove of not lessthan 0.1 μg/day/mm, the precursor having sufficient hydrophilicity asdetermined by a solubility in distilled water of not less than 1 μg/100ml, the, or each, blocking group being so linked to the 17β-oestradiolmoiety as to be readily removed from the 17β-oestradiol moiety in vivo;and the, or each, blocking group being so chosen as to yield a substancewhich is non-toxic to the female mammal, when removed from the17β-oestradiol moiety in vivo, with a biocompatible hydrophobicelastomeric polymer, a suitable cross-linking agent and a curingcatalyst to form a mix; and curing the mix to form a polymer matrix. 16.A process according to claim 15, in which the polymer matrix forms ahollow annulus and the process comprises the steps of forming a centralmember; combining the 17β-oestradiol precursor with a polymer, asuitable cross-linking agent and a curing catalyst to form a mix andcuring the mix to form the polymer matrix in the form of the hollowannulus surrounding the central member; and providing a sheathsurrounding the polymer matrix.
 17. An intravaginal drug delivery devicesuitable for administration to a female mammal, whenever prepared by theprocess claimed in claim
 15. 18. A method of using a 17β-oestradiolprecursor in a cylindrical intravaginal drug delivery device for releasein a substantially zero order pattern for at least three weeks, whichmethod comprises the step of incorporating in the drug delivery devicethe 17β-oestradiol precursor, wherein the 17β-oestradiol precursor is a17β-oestradiol moiety in which the, or each, hydroxyl group of the17β-oestradiol moiety is blocked by a blocking group, the precursor hassufficient lipophilicity as determined either by a solubility in liquidsilicone of not less than 0.1 mg/100 ml or by a standard k value asdefined hereinabove of not less than 0.1 μg/day/mm, the precursor hassufficient hydrophilicity as determined by a solubility in distilledwater of not less than 1 μg/100 ml, the, or each, blocking group is solinked to the 17β-oestradiol moiety as to be readily removed from the17β-oestradiol moiety in vivo, and the, or each, blocking group is sochosen as to yield a substance which is non-toxic to the female mammalwhen removed from the 17β-oestradiol moiety in vivo.
 19. A method ofreleasing a 17β-oestradiol precursor in a substantially zero orderpattern for a least three weeks, which method comprises the stepsof:incorporating the 17β-oestradiol precursor in a cylindricalintravaginal drug delivery device, the 17β-oestradiol precursor being a17β-oestradiol moiety in which the, or each, hydroxyl group of the17β-oestradiol moiety is blocked by a blocking group, the precursorhaving sufficient lipophilicity as determined either by a solubility inliquid silicone of not less than 0.1 mg/100 ml or by a standard k valueas defined hereinabove of not less than 0.1 μg/100 ml, the precursorhaving sufficient hydrophilicity, as determined by a solubility indistilled water or not less than 1 μg/100 ml, the, or each, blockinggroup being so linked to the 17β-oestradiol moiety as to be readilyremoved from the 17β-oestradiol moiety in vivo, the, or each, blockinggroup being so chosen as to yield a substance which is non-toxic to thefemale mammal when removed from the 17β-oestradiol moiety in vivo; andinserting the drug delivery device into a vagina of a female mammal forthe at least three weeks.
 20. An intravaginal drug delivery deviceaccording to claim 1 suitable for alleviating or preventing symptomsassociated with hypo-oestrogenism including hormone replacement therapy,in which the polymer matrix forms a core and the device is provided witha sheath surrounding the polymer matrix.
 21. A process according toclaim 15, in which the polymer matrix forms a core and the processadditionally comprises the step of providing a sheath surrounding thepolymer matrix.
 22. An intravaginal drug delivery device suitable foradministration to a female mammal, whenever prepared by the processclaimed in claim
 16. 23. An intravaginal drug delivery device accordingto claim 10, in which the precursor is 17β-oestradiol-3-acetate.
 24. Anintravaginal drug delivery device according to claim 11, in which theprecursor is 17β-oestradiol-17-acetate.